Synapse preservation and decreased glial reactions following ventral root crush (VRC) and treatment with 4‐hydroxy‐tempo (TEMPOL)

Abstract

Authors contributed equally to this work.Abbreviations: BSA, bovine serum albumin; CL, contralateral side to the lesion; CNS, central nervous system; IL, ipsilateral side to the lesion; PB, phosphate buffer; PBS, phosphate-buffered saline; PNS, peripheral nervous system; VRC, ventral root crush; IGF-1, insulin-like growth factor 1; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; TNFα, tumor necrosis factor alpha; IL-6, interleukin 6; iNOS, nitric oxide synthase; IL-1β, interleukin 1β; ROS, reactive oxygen species; NOS, reactive nitrogen species; TEMPOL, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxy; SOD, superoxide dismutase; VGLUT-1, vesicular glutamate transporter type 1; GAD65, glutamic acid decarboxylase 65. AbstractAstrogliosis and microglial reactions are correlated with the formation of scar tissue and synapse loss. 4-hydroxy-tempo (TEMPOL) is a reactive oxygen species scavenger with proven neuroprotective efficacy in experimental models of traumatic injury and cerebral ischemia. TEMPOL has not, however, been applied following ventral root lesions, which are particularly correlated with the degeneration of spinal motoneurons following brachial plexus injuries. Thus, the present study investigated the effects of TEMPOL on motoneurons and adjacent glial reactions, with a particular focus on the preservation of excitatory and inhibitory spinal circuits. Adult female Sprague Dawley rats were subjected to ventral root crush (VRC) at the lumbar intumescence. Animals were divided into the following experimental groups: (a) VRC-saline treatment; (b) VRC-TEMPOL treatment (12 mg/kg, n = 5), and (c) VRC-TEMPOL treatment (250 mg/kg, n = 5). The spinal cord tissue located contralateral to the lesion was used as the control. Fourteen days after lesioning, the rats were euthanized and the spinal cords were removed for motoneuron counting and immunolabeling with glial (GFAP and Iba-1) and synapse markers (synaptophysin, VGLUT-1, and GAD65). Although TEMPOL did not exert neuroprotective effects at the studied concentrations, the modulation of glial reactions was significant at higher doses.Thus, synaptophysin staining was preserved and, in particular, VGLUT-1-positive inputs were maintained, thereby indicating that TEMPOL preserved proprioceptive glutamatergic inputs without exacerbating the rate of motoneuron degeneration.Consequently, its administration with other efficient neuroprotective substances may significantly improve the outcomes following spinal cord lesioning. K E Y W O R D S gliosis, inflammation, motoneuron, spinal cord, TEMPOL, ventral root lesion | 521 SPEJO Et al.

Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1G93A mice

“…IFN β treatment further reduced glutamatergic immunolabeling by 45% in comparison to the vehicle counterpart. The same pattern of synaptic detachment has been described in axotomy models, where preferential 10.3389/fncel.2023.1211486 retraction of excitatory synapses after the injury is observed, reflecting a synaptic reorganization, to favor axonal regeneration (Lindå et al, 2000;Spejo et al, 2019). This is in line with the hypothesis that the increased expression of AMPAr in astrocytes by MHC-I upregulation is related to decreased glutamate concentration in the motoneuron vicinity, thus reducing excitotoxicity, resulting in motoneuron survival.…”

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

“…Moreover, the effects of quercetin, melatonin and curcumin have been explored in obese patients in different studies, but they have not proposed gliosis as an important comorbidity [ 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 ]. Other antioxidants that can be proposed as possible neuroprotectors in gliosis are resveratrol [ 214 , 215 , 216 ], epigallocatechin-3-gallate [ 217 ], 4-hydroxy-tempo (TEMPOL) [ 218 ], astilbin [ 219 ], 2-hydrazino-4,6-dimethylpyrimidine [ 220 ], L-carnitine and exendin-4 [ 221 , 222 ], simvastatin [ 223 ], creatine [ 224 ], ellagic acid [ 225 ], cannabidiol [ 226 ], celastrol [ 227 ], ebselen [ 228 ], Idenebone [ 229 ] and N-acetylcysteine [ 230 ].…”

EphB2 knockdown decreases the formation of astroglial‐fibrotic scars to promote nerve regeneration after spinal cord injury in rats

“…Although the formation of glial scar is in favor of axon regeneration in the central nervous system (CNS), 25 several latest reports show that decreased glial reaction and scar formation is beneficial to recovery from spinal cord injury. 26,27 After CNS injury, fibroblasts, pericytes, and inflammatory cells, in addition to astrocytes, participated in the formation of extracellular matrix. 10 However, fibrotic scars and glial scars together built astroglial-fibrotic scars, which had a negative effect on axon regeneration.…”